AND ABSTRACT Harnessing the immune system for the treatment of cancer through PD-1 checkpoint inhibitor has shown considerable promise in a number of solid tumors. Recently, the use of neoadjuvant PD-1 checkpoint blockade demonstrated prolonged overall survival in a randomized study of patients with recurrent glioblastoma. However, outcomes remain poor for these patients, with an observed median survival of 13.2 months and most patients succumbing to disease progression. Our group has found a novel way to overcome treatment resistance to adjuvant ?PD-1 monotherapy by employing concomitant transfer of bone marrow-derived hematopoietic stem and progenitor cells (HSC) with PD-1 checkpoint inhibition in preclinical models of CNS malignancies. We have demonstrated that HSCs co-transferred with immunotherapy significantly increases accumulation and significant activation of tumor-reactive T cells and tumor-associated dendritic cells (DC) within malignant glioma and medulloblastoma. Here we will dissect the mechanisms by which HSCs simultaneously modulate multiple pathways within the tumor microenvironment to potentiate anti-tumor immunity in preclinical models of cortical high grade glioma (KR158B) and Group 3 molecular subtype medulloblastoma (NSC). We have recently published that HSC + ?PD-1 overcomes treatment resistance to ?PD-1 in both f high grade glioma and cerebellar medulloblastoma which are tumors with distinct genetic backgrounds and anatomic location. We believe that this therapy has unifying mechanisms that transcends the differences in the types of malignant brain tumors and their anatomical location in these orthotopic models. The major impact of our study is that we have discovered a clinically applicable method of overcoming treatment resistance to ?PD-1 in multiple refractory brain tumors. Importantly, we believe that combinatorial HSC + ?PD-1 dramatically reduces modulatory pathways within brain tumors while displacing endogenous suppressor cells. This leads to the observed subsequent increases in anti- tumor T cell activation within the tumor microenvironment. The characterization and development of a singular intravenously-delivered immunotherapeutic that can target multiple immune regulatory pathways within several distinct brain tumors is highly significant and clinically relevant. Our HYPOTHESIS is that HSCs overcome treatment resistance to PD-1 checkpoint blockade through altering the cell fate differentiation of multi-lineage cellular compartments within the tumor microenvironment. Towards this end, the AIMS of this project are to:
AIM 1. Determine the mechanism by which HSC + ?PD-1 potentiate immune activation within the tumor microenvironment;
AIM 2. Identify pathways that allow escape from HSC + ?PD-1 therapy;
AIM 3. Determine strategies to enhance the efficacy of HSC + ?PD-1.
The treatment of solid tumors with immune checkpoint inhibitors is promising, yet understanding treatment resistance against brain malignancies is paramount. We have found a novel way to overcome treatment resistance to anti-PD-1 monotherapy by employing concomitant transfer of bone marrow-derived hematopoietic stem and progenitor cells (HSC) with PD-1 checkpoint inhibition in preclinical models of high grade glioma and medulloblastoma. The project goals are to dissect and understand treatment resistance to HSC + PD-1 therapy in subjects with non-curative treatment.
